Diabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetic retinopathy [
DME is mainly due to an abnormal vascular permeability involving vascular endothelial growth factor (VEGF). Intravitreal anti-VEGF therapy is currently one of the treatments of DME along with corticosteroids: in 2012, ranibizumab has been approved by the Food & Drug Administration (FDA) following the RISE and RIDE studies [
Thus, the first approved therapy with an intravitreally applied agent used in our practice in DME patients was ranibizumab because of its earlier availability. In our previously published real-life series of patients treated with ranibizumab, 18% did not respond to 3 intravitreal injections and showed a visual gain < 5 letters and an anatomical improvement in central retinal thickness (CRT) < 10% of the initial CRT [
Unlike ranibizumab, aflibercept binds not only VEGF-A but also VEGF-B and placental growth factor (PlGF) [
The aim of this study was to assess the short-term outcomes following a switch from ranibizumab or dexamethasone therapy to aflibercept in the treatment of refractory DME.
A retrospective study was conducted in a tertiary center specialized in imaging and treatment of retinal diseases. All consecutive patients diagnosed with DME and treated with ranibizumab (0.5 mg) and/or dexamethasone (0.7 mg) and subsequently switched to aflibercept (2.0 mg) between June 2015 and August 2016 were included. Indications for switching to aflibercept included persistent DME under a previous well-conducted treatment, defined as no reduction, incomplete resolution (<10% improvement of central retinal thickness (CRT)), increase in central subfield thickening, or persistence of central cysts on SD-OCT, considered as significant by the investigator after a loading phase of at least 3 injections. The choice of switching was at the discretion of the investigator. Decision for switching to aflibercept after dexamethasone was taken when these same anatomical criteria were observed at the second visit (8 weeks) after at least one dexamethasone injection.
This study was conducted in accordance with the tenets of the Declaration of Helsinki, and an informed consent was obtained from all patients. Approval was obtained from the France Macula Federation ethical committee (FMF 2017-138).
Inclusion criteria were as follows: patients with type 1 or 2 diabetes, with persistent DME defined by a loss of the foveal pit, and a CRT > 300
Exclusion criteria were as follows: other ocular conditions impairing vision or complication of diabetic retinopathy (tractional retinal detachment, vitreous hemorrhage), fewer than three ranibizumab injections prior to the switch to aflibercept, and incomplete imaging or clinical data.
All patients underwent a complete baseline ophthalmological examination including VA on ETDRS chart, slit-lamp examination, fundus imaging, and SD-OCT. VA was measured monthly, and SD-OCT scans were assessed 4 weeks after the third injection and at month 6 of follow-up. Baseline VA was defined as the initial VA before any intravitreal treatment and preswitch VA as the VA just before switching to aflibercept. All patients were assessed every 4 weeks after the 3 initial aflibercept injections and treated on an as-needed, pro re nata (PRN), regimen in case of recurrence based on functional (VA < 78 letters or 20/32) and anatomical parameters (CRT > 300
SD-OCT scans were obtained using the Cirrus 5000 (ZEISS, Meditec) and were reviewed by the investigator to document the presence of intraretinal/subretinal fluid and decide if the patient needed additional injections.
The primary endpoint was the mean variation in VA between the preswitch time and month 6 (M6) after the switch.
Secondary endpoints were VA after 3 initial intravitreal injections of aflibercept (M3), CRT at 3 and 6 months, and number of injections.
Statistical analysis was performed using a
A
Twenty-nine eyes were screened but the data at 6 months were not available for 4 eyes that were excluded for the following reasons: patient dropout (2 eyes) and 2 eyes underwent cataract surgery between 3 and 6 months after the first injection of aflibercept. Thus, 25 eyes of 21 patients met the inclusion criteria and were included. Patient mean age was 63.1 ± 10.8 years (range: 33–83 years). There was a slight female predominance with 13 women included (62%).
Baseline characteristics are presented in Table
Patient baseline demographics and clinical characteristics.
Patient demographics and clinical characteristics ( |
||
---|---|---|
Gender | 13 female/8 male | |
Age (years) | Median (min–max) | 64 (33–83) |
Diabetes | Type 1, |
2 (9.6) |
Type 2, |
19 (90.4) | |
Insulin/ODT/ODT + insulin ( |
12/3/6 | |
HbA1c levels (%) | Median (min–max) | 8.3 (7.5–10.7) |
High blood pressure, |
18 (78.3) | |
Pan retinal photocoagulation, |
20 (75), 2 ongoing | |
Lens |
Phakic | 12 (48) |
IOL | 13 (52) | |
Ranibizumab ( |
Median number of injections (min–max) | 9.5 (3–15) |
Ozurdex only ( |
Median number of dexamethasone injections | 1 |
Ranibizumab + Ozurdex ( |
Median number of dexamethasone injections (min–max) | 1 (1–3) |
Macular laser history ( |
2 |
ODT: oral diabetes treatment.
Before inclusion, 23 eyes received a mean number of 9 ± 4.6 (median: 9.5, range: 3–15 injections) ranibizumab injections, and among them, 6 eyes received a mean number of 1.5 (median: 1, range: 1–3 injections) dexamethasone implants following ranibizumab treatment. Two eyes received only one dexamethasone implant before switching to aflibercept. The mean follow-up duration was 2.2 ± 0.2 (1.9–2.6) months at M3 and 5.7 ± 0.5 (5. 2–7) months at M6 after the first aflibercept injection.
The mean baseline VA before any intravitreal injection was of 52.9 ± 16.5 letters and the mean VA prior to the switch was of 57.1 ± 19.6 (+4.2 letters of visual gain). VA improved to 65.5 ± 16.4 letters (
Functional outcomes: visual acuity before any intravitreal injection (baseline) and before and after switch to aflibercept at M3 and M6.
Baseline | Preswitch | M3 postswitch | M6 postswitch | |
---|---|---|---|---|
Number of eyes | 25 | 25 | 25 | 25 |
Mean letter score (SD) | 52.9 (16.5) | 57.1 (19.6) | 65.5 (16.4) | 65.1 (15.2) |
|
2.914 | |||
|
0.04 |
|||
Mean VA change from preswitch (SD) | 8.4 (14.1) | 8 (15.1) | ||
|
0.006 |
0.01 |
||
Mean VA change from baseline (SD) | 4.2 (3.3) | 12.6 (11.6) | 12.2 | |
|
0.34 | <0.0001 |
0.0003 |
Change in visual acuity (ETDRS chart) over 6 months of follow-up after switch to aflibercept. Box plots representing at each time point the distribution of data from bottom to top: minimum, first quartile, median, third quartile, and maximum.
The mean baseline CRT before any intravitreal injection was 532 ± 186.2
Anatomical outcomes: central retinal thickness before any intravitreal injection (baseline) and before and after switch to aflibercept at M3 and M6.
Baseline | Preswitch | M3 postswitch | M6 postswitch | |
---|---|---|---|---|
Number of eyes | 25 | 25 | 25 | 25 |
Mean CRT in |
532 (186.2) | 470.8 (129.9) | 315.6 (89.7) | 303.3 (59.1) |
|
21.47 | |||
|
0.0013 |
|||
Mean CRT change from preswitch in |
−155.2 (144.7) | −167.5 (149.3) | ||
|
<0.0001 |
<0.0001 |
||
Mean CRT change from baseline in |
−61.2 (176) | −216.4 (226.1) | −228.7 (212.2) | |
|
0.07 | <0.0001 |
<0.0001 |
CRT: central retinal thickness;
Change in central retinal thickness over 6 months of follow-up after switch to aflibercept. Box plots representing at each time point the distribution of data from bottom to top: minimum, first quartile, median, third quartile, and maximum.
A subgroup analysis was performed to determine the percentage of eyes with a CRT < 300
Subgroup analysis according to CRT < 300 or ≥300
Final CRT (M6) | |||
---|---|---|---|
CRT < 300 microns (group 1) | CRT > 300 microns (group 2) |
| |
Number of eyes | 15 | 10 | |
Mean letter score at baseline prior to any injection (SD) | 50.7 (17.3) | 55.7 (15.9) | 0.48 |
Mean letter score preswitch (SD) | 55.9 (20.4) | 59 (19.1) | 0.7 |
Mean letter score postswitch M3 (SD) | 67 (14) | 63.4 (20.1) | 1 |
Mean letter score postswitch M6 (SD) | 67 (14.8) | 62.2 (16.3) | 0.45 |
Mean VA change from preswitch (SD) | 11.1 (16.2) | 3.2 (12.5) | 0.2 |
F | 7.38 | 0.96 | |
|
0.003 |
0.4 | |
|
0.02 |
0.44 |
ANOVA test was performed to assess significance between VA at baseline, preswitch, M3, and M6 after switch to aflibercept within each group. a
After 6 months of follow-up, 60% of the eyes had a CRT < 300
At 6 months, 40% of the eyes still had a CRT > 300
The second subgroup analysis (Tables
Subgroup analysis of the impact of the preswitch VA (< or ≥70 letters) on VA.
Preswitch visual acuity | |||
---|---|---|---|
VA < 70 letters (group 1) | VA ≥ 70 letters (group 2) |
| |
Number of eyes | 17 | 8 | |
Mean letter score at baseline prior to any injection (SD) | 48.1 (17.2) | 63.9 (7.9) | 0.007 |
Mean letter score preswitch (SD) | 47.4 (15.8) | 77.7 (5) | 0.001 |
Mean letter score postswitch M3 (SD) | 59 (15.8) | 79.4 (5.3) | 0.001 |
Mean letter score postswitch M6 (SD) | 58 (13) | 80.1 (5.6) | 0.001 |
Mean VA change from preswitch (SD) | 10.6 (17.4) | 2.4 (5.7) | 0.2 |
|
5.6 | 15.37 | |
|
0.004 |
0.03 |
|
|
0.02 |
0.5 |
ANOVA test was performed to assess significance between VA at baseline, preswitch, M3, and M6 after switch to aflibercept within each group. a
Subgroup analysis of the impact of the preswitch VA (< or ≥70 letters) on CRT.
Preswitch visual acuity | |||
---|---|---|---|
VA < 70 letters (group 1) | VA ≥ 70 letters (group 2) |
| |
Number of eyes | 17 | 8 | |
Mean CRT in |
582.7 (201.3) | 430.5 (96.8) | 0.03 |
Mean CRT in |
495.2 (142.7) | 418.9 (82) | 0.28 |
Mean CRT postswitch M3 (SD) | 312.7 (106) | 321.6 (40.6) | 0.47 |
Mean CRT postswitch M6 (SD) | 301.8 (69.1) | 306.4 (32.5) | 0.62 |
F | 18.21 | 9.42 | |
|
<0.0001 |
0.003 |
|
|
0.0002 |
0.008 |
ANOVA test was performed to assess significance between CRT at baseline, preswitch, M3, and M6 after switch to aflibercept within each group. a
Eight eyes were previously treated with intravitreal dexamethasone implant before switching to aflibercept. Their median baseline VA was 45 (15–54) letters, and their preswitch median VA was 46.5 (5–74) letters. After switching, they improved their median VA to 54.5 (24–85) at M3 (
Their median baseline CRT was 477
The functional and anatomical outcomes among patients treated by ranibizumab monotherapy, dexamethasone monotherapy, or combined monotherapy before switching to aflibercept are presented in Table
Subanalysis assessing functional and anatomical outcomes depending on treatment received before switch (ranibizumab monotherapy, dexamethasone monotherapy, or combined therapy).
|
Baseline | Preswitch | M3 | M6 |
|
| |
---|---|---|---|---|---|---|---|
|
|||||||
Ranibizumab monotherapy median (min–max) | 17 | 59 (15–74) | 65 (37–85) | 74 (35–85) | 70 (50–85) | 9.747 | 0.0002 |
Dexamethasone monotherapy median (min–max) | 2 | 64 (54–74) | 60 (46–74) | 60 (35–85) | 63.5 (44–83) | NA | NA |
Combined therapy median (min–max) | 6 | 39.5 (15–50) | 43.5 (5–53) | 54.5 (24–74) | 54.5 (35–74) | 2.5 | 0.15 |
|
0.09 | 0.0002 |
0.0035 |
||||
|
0.004 |
0.03 |
|||||
|
|||||||
Ranibizumab monotherapy median (min–max) | 17 | 513 (376–831) | 476 (315–660) | 324 (208–388) | 296 | 24.75 | 0.0001 |
Dexamethasone monotherapy median (min–max) | 2 | 373 (306–440) | 531 (366–696) | 468 (313–623) | 314.5 (299–330) | NA | NA |
Combined therapy median (min–max) | 6 | 540 (350–1088) | 390.5 (327–677) | 251.5 (204–420) | 272.5 (208–388) | 5.019 | 0.053 |
|
0.08 | <0.0001 |
<0.0001 |
||||
|
<0.0001 |
<0.0001 |
No serious adverse event following intravitreal injections was noted in this study.
In this study, we showed a rapid anatomical and functional improvement in eyes with persistent DME that poorly responded to ranibizumab and/or dexamethasone after a switch to aflibercept.
Only a few studies have assessed the outcomes of a switch to aflibercept after chronic anti-VEGF therapy for persistent DME. In a prospective study, Wood et al. [
Another recent retrospective study [
In our study, when a switch was decided, we made the choice to prescribe a complete treatment protocol including 3 monthly aflibercept injections before patient assessment as we considered that the switch required a new loading phase of injections.
A more recent retrospective study [
In our study, we found a functional and anatomical improvement 6 months after aflibercept switch. We assumed that this result could be due to our strict retreatment criteria mainly based on anatomical features instead of criteria based on the functional improvement only and to the systematic prescription of 3 monthly injections when the switch was decided. Indeed, we considered that a switch could be relevant even when the vision was improved although some fluid was still present in the retina. This assumption was confirmed, in particular in patients with a final CRT < 300
A subgroup analysis was performed to determine the impact of the preswitch VA. We found a higher final VA change of +10.6 letters when the preswitch VA was <70 letters, but with a lower final VA of 58 letters at 6 months versus a gain of only +2.4 letters in the group with a preswitch VA ≥ 70 letters, with a much higher final VA of 80.1 letters at 6 months, without any difference in CRT between both groups at preswitch, M3, and M6.
The slight visual gain in the group with the highest preswitch VA could be explained by the ceiling effect [
However, our study was one of the first “real-life” study assessing the switch to aflibercept in DME resistant to ranibizumab at the dose of 0.5 mg. Similarly, for instance, Rahimy et al. [
Even with a higher dose of ranibizumab, 0.5 mg versus 0.3 mg, DME was still persistent in our series. After the switch to aflibercept and 6 months of follow-up, 60% of the eyes had a CRT < 300
Switching to dexamethasone implant has shown good functional and anatomical outcomes after ranibizumab failure in DME treatment [
Our real-life short-term results are consistent with those of the VIVID and VISTA studies [
In case of drug switch in DME treatment, it is easy to understand that a switch from corticosteroids, when ineffective, to anti-VEGF may improve CRT and VA by restoring the inner blood-retinal barrier through the differential effects of these various treatment classes. However, in cases of switch from ranibizumab to aflibercept, two anti-VEGF agents, the efficacy of aflibercept could be due either to a switch effect in case of autoantibody development to prior anti-VEGF therapy [
Our study is limited by its retrospective design, the absence of a control group (ranibizumab monotherapy, dexamethasone monotherapy, or combination of both) to compare outcomes of eyes not switched to aflibercept and receiving their initial treatment for an extended period of time. The follow-up of 6 months was not intended to observe the long-term effect of the treatment but mainly to confirm the efficacy of aflibercept treatment in case of failure of other therapies in DME.
In conclusion, despite its limitations, this study provides a potentially useful clinical insight into DME not responding to ranibizumab and/or dexamethasone in a real-life setting. Our results supports early DME treatment switch before patients experience a severe vision loss when the first therapy is not effective, since 60% of our patients achieved a complete fluid resolution and a good visual improvement.
This study was presented as a poster at the ARVO annual meeting, Baltimore, May 2017.
Antoine Herbaut, Lise Qu-Knafo, and Bahram Bodaghi have nothing to disclose. Franck Fajnkuchen and Sylvia Nghiem-Buffet are consultants for Allergan, Bayer, and Novartis outside of the submitted work. Audrey Giocanti-Auregan is a consultant for Allergan, Alimera, Bayer, and Novartis outside of the submitted work.
This study was supported by AVOPH (Association for Research in Vision and Ophthalmology; Avicenne Hospital, 125 rue de Stalingrad, 93000 Bobigny, France).